One of intractable cancer (malignant neoplasm) treatment techniques is immunotherapy that causes regression of a cancer cell by boosting the immune system in an individual patient. The important point is to find a method for encouraging the immune system to recognize a cancer cell as foreign matter and inducing an immunocyte having aggressiveness against the cancer cell.
Key immunocytes associated with antitumor immunity include a cytotoxic T cell expressing a CD8 cell surface protein (CD8-positive T cell) and a T cell expressing a CD4 cell surface protein (CD4-positive T cell). The CD8-positive T cell, when activated, lyses a cell that presents an antigen binding to an HLA Class 1 molecule. The CD4-positive T cell is a cytokine-secreting Th cell that provides the CD8-positive T with a helper function, i.e. cell induction and preservation, when it is activated by a macrophage and/or a dendritic cell presenting an antigen by an HLA Class II molecule. Conventionally, Th cells are classified into Th1 cell (producing INF-γ, etc.), Th2 cell (producing IL-4, etc.) and Th0 cell (known as low cytokine producing ability or producing both INF-γ and IL-4, etc.), and respective roles thereof are being specifically provided. The CD4-positive T cell can be provided with effector functions by its indirect mechanism against an MHC Class II molecule negative tumor (MHC Class II-tumor), e.g., via activation of a macrophage, or direct mechanism against an MHC Class II positive tumor (MHC Class II-positive tumor).
Conventional T cell researches in human cancer immunotherapy focus on identification and induction of CD8-positive HLA Class I restricted CTL response (Patent Document 1). With regard to CD4-positive T cell, a report on the identification of a tyrosinase cancer antigen and its epitope corresponding to a CD4-positive T cell is given (Patent Document 2). Tyrosinase is known as the only antigen specific to melanoma associative tissues, which binds to an MHC Class II molecule expressed in normal cells and tumor cells of melanocyte line and presented as a specific target of a CD4-positive melanoma-reactive T cell (Non-Patent Document 1). However, due to its expression only in limited types of tumor, the tyrosinase antigen cannot be assuredly defined as a promising cancer antigen in cancer immunotherapy.
A recent report presents a gene family encoding a tumor-specific antigen that is recognized by a CD8-positive T cell (MAGE) (Non-Patent Documents 2 to 4, and Patent Documents 3 and 4). This MAGE gene family consists of about 12 members expressed in various types of tumor. According to a study on an MAGE-A3 thereof, the MAGE-A3 is a peptide whose partial peptide fragment is presented by an HLA Class I molecule (Patent Document 5) and another partial peptide fragment binds to an HLA Class II molecule (Patent Documents 6 and 7).
Although it was found that the MAGE-A3 includes an HLA Class II-binding peptide, many individual patients express no appropriate HLA molecule, resulting in unsuccessful therapies, such as activation of a helper T cell by the MAGE-A3 peptide. Therefore, identification of more tumor-associated antigens, which bind to an MHC Class II molecule and include an epitope recognized by a CD4-positive T cell, is significantly required.
As another MAGE family, MAGE-A4 is a tumor-specific antigen whose all 317 constituents are amino acid residues (SEQ ID No: 3). MAGE-A4 is highly expressed in many tumor-histologic cases such as melanoma, esophageal cancer, head and neck cancer and lung cancer, but such expression is not observed in normal cells other than testis and placenta (Non-Patent Document 5).
With regard to MAGE-A4 antigenicity, it is reported that MAGE-A4 amino acid sequence of No. 143 to 151 presents an epitope recognized by a CD8-positive T cell (Non-Patent Document 6). Also, MAGE-A4's affinity to gankyrin is described (Patent Document 8), and more specifically, a portion thereof corresponding to amino acids of No. 211 to 317 at C terminus of MAGE-A4 is associated with the affinity to gankyrin. Meanwhile, it is also reported that a C terminus portion, containing 97 amino acid residues from No. 211 amino acid of MAGE-A4, has no ability to bind to gankyrin.
Non-Patent Document 1: Topalian, S. L. et al., Proc. Natl. Acad. Sci. USA, Vol. 91, pp. 9461-9465, 1994
Non-Patent Document 2: Plaen et al., Immunogenetics, Vol. 40, pp. 360-369, 1994
Non-Patent Document 3: Traversari et al., Immunogenetics, Vol. 35, p 145, 1992
Non-Patent Document 4: van der Bruggen et al., Science, Vol. 254, p 1643, 1991
Non-Patent Document 5: Duffour M. T. et al., Eur. J. Immunol., Vol 29, pp. 3329-3337, 1999
Non-Patent Document 6: Yoshihiro M. et al., Clin. Cancer Res., Vol 121, pp. 5581-5589, 2005
Patent Document 1: WO 95/19783
Patent Document 2: WO 97/11669
Patent Document 3: PCT/US 92/04,354
Patent Document 4: U.S. Pat. No. 5,342,774
Patent Document 5: U.S. Pat. No. 5,591,430
Patent Document 6: U.S. Pat. No. 5,965,535
Patent Document 7: PCT/US 99/21,230
Patent Document 8: Japanese Unexamined Patent Application Publication No. 2004-123752